Impact of Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions on malaria control worldwide: a systematic review and meta-analysis

Abstract

Background Deletion of pfhrp2 and/or pfhrp3 genes cause false negatives in malaria rapid diagnostic test (RDT) and threating malaria control strategies. This systematic review aims to assess the main methodological aspects in the study of pfhrp2 and pfhrp3 gene deletions and its global epidemiological status, with special focus on their distribution in Africa; and its possible impact in RDT. Methods The systematic review was conducted by examining the principal issues of study design and methodological workflow of studies addressing pfhrp2 deletion. Meta-analysis was applied to represent reported prevalences of pfhrp2 and pfhrp3 single and double deletion in the World Health Organization (WHO) region. Pooled-prevalence of deletions was calculated using DerSimonnian-Laird random effect model. Then, in-deep analysis focused on Africa was performed to assess possible variables related with these deletions. Finally, the impact of these deletions in RDT results was analysed combining reported information about RDT sensitivity and deletion prevalences. Results 49 articles were included for the systematic review and 37 for the meta-analysis, 13 of them placed in Africa. Study design differs significantly, especially in terms of population sample and information reported, resulting in high heterogeneity between studies that difficulties comparisons and merged conclusions. Reported prevalences vary widely in all the WHO regions, significantly higher deletion were reported in South-Central America, following by Africa and Asia. Pfhrp3 deletion is more prevalent (43% in South-Central America; 3% in Africa; and 1% in Asia) than pfhrp2 deletion (18% in South-Central America; 4% in Africa; and 3% in Asia) worldwide. In Africa, there were not found differences in deletion prevalence by geographical or population origin of samples. The prevalence of deletion among false negatives ranged from 0 to 100% in Africa, but in Asia and South-Central America was only up to 90% and 48%, respectively, showing substantial relation between deletions and false negatives. Conclusion The concerning prevalence of pfhrp2, pfhrp3 and pfhrp2/3 gene deletions, as its possible implications in malaria control, highlights the importance of regular and systematic surveillance of these deletions. This review has also outlined that a standardized methodology could play a key role to ensure comparability between studies to get global conclusions.

The prognostic and diagnostic value of intraleukocytic malaria pigment in patients with severe falciparum malaria

“…Blood slide microscopy gives quantitative information which is not vulnerable to technical errors or to mutations in the parasite target genes (e.g. PfHRP2 mutations, which can cause false RDT negativity 27,28 speed and ease of assessment (see 29 ) and they provide valuable prognostic information. In addition to the malaria parasite count (the proportion of red cells containing one or more parasites), the stage of asexual parasite development can be assessed 8 and the proportion of leukocytes containing ingested malaria pigment in the blood slide can be counted 9 .…”

Deletion patterns, genetic variability and protein structure of pfhrp2 and pfhrp3: implications for malaria rapid diagnostic test in Amhara region, Ethiopia

“…Another explanation for the wide range of deletion prevalence reported could be the differences in genotyping approach, for example, a recent study in Ethiopia only analysed samples with low or without HRP2 signal by multiplex bead assay [ 47 ]. That makes it essential to generalized technical strategies across studies [ 48 ]. Potential false negatives caused by pfhrp2 deletions could be avoided by cross-reaction with pfHRP3 as this can be detected by HRP2-based RDT in the absence of pfHRP2 [ 4 ].…”

Gene Coverage Count and Classification (GC3): a locus sequence coverage assessment tool using short-read whole genome sequencing data, and its application to identify and classify histidine-rich protein 2 and 3 deletions in Plasmodium falciparum

“…Of note is the high prevalence of all deletions, and especially hrp3 deletions among Brazilian samples. Deletions in hrp2/3, and reports of high deletion prevalence, were first observed in the American continent [8,9,17,19,[40][41][42], especially in the hrp3 locus [8,43]. Overall, GC 3 can appropriately process and analyse publicly available WGS datasets from a variety of genomic studies.…”

“…In particular, full deletions, as well as some partial deletions, in one or both of these genes eliminate HRP2 and/or HRP3 signal on RDTs, preventing accurate malaria diagnosis. Previous estimates of hrp2/3 deletion prevalence report higher frequencies in South and Central America, followed by Africa, then Asia and Oceania [ 17 ]. Low-transmission areas with high treatment rates, characteristics often found in elimination settings, are especially at risk for the spread of strains with hrp2/3 gene deletions, as models show that, under those conditions, strains with hrp2/3 deletions have a strong fitness advantage over those with intact genes [ 18 ].…”